Kavanagh Tomas, Balcomb Kaleah, Ahmadi Rastegar Diba, Lourenco Guinevere F, Wisniewski Thomas, Halliday Glenda, Drummond Eleanor
Brain and Mind Centre and School of Medical Sciences, University of Sydney, Camperdown, New South Wales, Australia.
Center for Cognitive Neurology and Departments of Neurology, Pathology and Psychiatry, Grossman School of Medicine, New York University, New York, New York, USA.
Brain Pathol. 2025 May;35(3):e13305. doi: 10.1111/bpa.13305. Epub 2024 Oct 1.
Tau interacts with multiple heterogeneous nuclear ribonucleoproteins (hnRNPs)-a family of RNA binding proteins that regulate multiple known cellular functions, including mRNA splicing, mRNA transport, and translation regulation. We have previously demonstrated particularly significant interactions between phosphorylated tau and three hnRNPs (hnRNP A1, hnRNP A2B1, and hnRNP K). Although multiple hnRNPs have been previously implicated in tauopathies, knowledge of whether these hnRNPs colocalize with tau aggregates or show cellular mislocalization in disease is limited. Here, we performed a neuropathological study examining the colocalization between hnRNP A1, hnRNP A2B1, hnRNP K, and phosphorylated tau in two brain regions (hippocampus and frontal cortex) in six disease groups (Alzheimer's disease, mild cognitive impairment, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, and controls). Contrary to expectations, hnRNP A1, hnRNP A2B1, and hnRNP K did not colocalize with AT8-immunoreactive phosphorylated tau pathology in any of the tauopathies examined. However, we did observe significant cellular mislocalization of hnRNP A1, hnRNP A2B1 and hnRNP K in tauopathies, with unique patterns of mislocalization observed for each hnRNP. These data point to broad dysregulation of hnRNP A1, A2B1 and K across tauopathies with implications for disease processes and RNA regulation.
tau蛋白与多种不均一核核糖核蛋白（hnRNPs）相互作用，hnRNPs是一类RNA结合蛋白家族，可调节多种已知的细胞功能，包括mRNA剪接、mRNA转运和翻译调控。我们之前已经证明磷酸化tau蛋白与三种hnRNPs（hnRNP A1、hnRNP A2B1和hnRNP K）之间存在特别显著的相互作用。尽管之前已经有多种hnRNPs被认为与tau蛋白病有关，但关于这些hnRNPs是否与tau蛋白聚集体共定位或在疾病中表现出细胞定位错误的了解仍然有限。在这里，我们进行了一项神经病理学研究，检查了六个疾病组（阿尔茨海默病、轻度认知障碍、进行性核上性麻痹、皮质基底节变性、皮克病和对照组）的两个脑区（海马体和额叶皮质）中hnRNP A1、hnRNP A2B1、hnRNP K与磷酸化tau蛋白之间的共定位情况。与预期相反，在所检查的任何tau蛋白病中，hnRNP A1、hnRNP A2B1和hnRNP K均未与AT8免疫反应性磷酸化tau蛋白病变共定位。然而，我们确实在tau蛋白病中观察到了hnRNP A1、hnRNP A2B1和hnRNP K明显的细胞定位错误，并且每种hnRNP都观察到了独特的定位错误模式。这些数据表明，hnRNP A1、A2B1和K在tau蛋白病中广泛失调，这对疾病进程和RNA调控具有重要意义。
